Physiological Functions of Amyloid Precursor Proteins

Amyloid precursor proteins (APPs) are evolutionarily conserved membrane glycoproteins that undergo complex proteolytic processing to yield fragments with diverse biological activities. Beyond their role as precursors of amyloid-β, APPs regulate proteostasis by modulating autophagy and protein synthesis, influence mitochondrial function and lipid metabolism, and act as receptors or co-receptors in cellular signalling. In the nervous system, APPs contribute to synaptic maturation and plasticity by interacting with glutamate receptors, supporting neurite outgrowth and long-term potentiation. They also coordinate neurogenesis by balancing progenitor self-renewal and differentiation through transcriptional and WNT-dependent pathways. In glial cells, APPs supply metal ions essential for reactive oxygen species signalling that underpins memory formation. Secreted APP fragments promote neuroprotection and may counteract age-related decline in neuronal resilience. These multifaceted functions underscore APPs as central hubs in neural development, homeostasis and response to stress, with implications for understanding ageing and neurodegenerative disorders.

Research from Nature Portfolio

Recent studies have revealed a conserved role for APP in maintaining proteome integrity during ageing. In invertebrate and mammalian models, loss of APP orthologues leads to dysregulation of translation, mitochondrial dynamics, lipid and nucleic acid metabolism, and impaired autophagy via altered TGFβ signalling. Restoration of APP function rescues autophagic flux and mitigates proteotoxic stress in tauopathy models. In parallel, work in insect memory circuits has uncovered an astrocyte-to-neuron hydrogen peroxide pathway essential for long-term memory. Acetylcholine-activated astrocytes produce superoxide, which is converted to hydrogen peroxide by extracellular dismutase; this signal enters neurons via copper ions delivered by APP. Disruption of APP-dependent copper supply or inhibition of astrocytic receptors impairs memory consolidation, linking APP to glial-neuronal redox communication.

Physiological Functions of Amyloid Precursor Proteins publication trend

The graph below shows the total number of articles in physiological functions of amyloid precursor proteins across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid precursor protein (APP): A transmembrane glycoprotein processed by secretases to generate signalling and metabolic fragments.

Proteostasis: The maintenance of cellular protein homeostasis through synthesis, folding, trafficking and degradation pathways.

Autophagy: A lysosome-mediated degradation process that recycles cellular components and removes damaged organelles or proteins.

N-methyl-D-aspartate receptor (NMDAR): A subtype of glutamate receptor involved in synaptic plasticity and memory, composed of GluN1 and GluN2 subunits.

WNT signalling: A conserved pathway that regulates gene expression, cell proliferation and differentiation during development and tissue homeostasis.

Hydrogen peroxide (H2O2): A reactive oxygen species that can function as a signalling molecule in neuronal plasticity and memory processes.

References

1. Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging. Nature Communications (2023).
2. Astrocyte-to-neuron H2O2 signalling supports long-term memory formation in Drosophila and is impaired in an Alzheimer’s disease model. Nature Metabolism (2025).
3. The temporal balance between self-renewal and differentiation of human neural stem cells requires the amyloid precursor protein. Science Advances (2023).
4. Age‐dependent NMDA receptor function is regulated by the amyloid precursor protein. Aging Cell (2023).
5. A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis*. Journal of Biological Chemistry (2016).
6. Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα. Frontiers in Molecular Neuroscience (2017).